Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein

Plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins. Since CETP regulates the plasma levels of HDL, cholesterol and the size of HDL particles, CETP is considered to be a key protein in reverse cholesterol transport, a protective system against atherosclerosis. CETP, as well as plasma phospholipid transfer protein, belongs to members of the lipid transfer/ lipopolysaccharide-binding protein (LBP) gene family, which also includes the lipopolysaccharide-binding protein (LBP) and bactericidal/permeability-increasing protein. Although these four proteins possess different physiological functions, they share marked biochemical and structural similarities. The importance of plasma CETP in lipoprotein metabolism was demonstrated by the discovery of CETP-deficient subjects with a marked hyperalphalipoproteinemia (HALP). Two common mutations in the CETP gene, intron 14 splicing defect and exon 15 missense mutation (D442G), have been identified in Japanese WALP patients with CETP deficiency. The deficiency of CETP causes various abnormalities in the concentration, composition, and functions of both HDL and low density lipoprotein. Although the pathophysiological significance of CETP in terms of atherosclerosis has been controversial, the in vitro experiments showed that large CE-rich HDL particles in CETP deficiency are defective in cholesterol efflux. Epidemiological studies in Japanese-Americans and in the Omagari area where HALF subjects with the intron 14 splicing defect of CETP gene are markedly frequent, have shown an increased incidence of coronary atherosclerosis in CETP-deficient patients. The current review will focus on the recent findings on the molecular biology and pathophysiological aspects of plasma CETP, a key protein in reverse cholesterol transport. (C) 2000 Elsevier Science B.V. All rights reserved.